Skin preparation comprising a tocopherol derivative for external application

ABSTRACT

The present invention relates to a skin preparation for external application, comprising a tocopherol aminoalkylcarboxylate ester having a substituent on the N atom and/or a salt thereof. The preferable tocopherol aminoalkylcarboxylate ester in the present invention is one or more compound selected from α-tocopherol derivatives, β-tocopherol derivatives, γ-tocopherol derivatives and δ-tocopherol derivatives. The present invention also relates to a cosmetic material comprising the skin preparation for external application.

This application is an application filed under 35 U.S.C. 111(a) claimingpursuant to 35 U.S.C. 119 (e) of the filing date of ProvisionalApplication 60/359,334 on Feb. 26, 2002, Provisional Application60/373,579 on Apr. 19, 2002, pursuant to 35 U.S.C. 111(b).

TECHNICAL FIELD

The present invention relates to a skin preparation for externalapplication and a cosmetic material, characterized in that a tocopherolaminoalkylcarboxylate ester having a substituent on the N atom and/or asalt thereof is blended.

BACKGROUND ART

Tocopherols (e.g., α-tocopherol, β-tocopherol, γ-tocopherol,δ-tocopherol) known as vitamin E and derivatives thereof such astocopherol acetate and tocopherol nicotinate are known to provideefficacy and effect such as activities of antioxidation, vital membranestabilization, immunoactivation and acceleration of blood circulationand have been long blended in medical preparations, cosmetics, samplesand the like.

However, these compounds are oil-soluble and cannot be uniformlydispersed in an aqueous solution or an emulsion. In the case ofpreparing a medical or cosmetic product in the solubilized or emulsionstate, a nonionic surfactant is generally used to enable uniformdispersion, however, some nonionic surfactants are highly irritating orgive rise to environmental pollution and therefore, in view of safety,use of the nonionic surfactant is considered undesirable and improvementis demanded in this point.

Furthermore, tocopherols in the simple form are readily oxidized andunstable and therefore, are used as an organic acid ester derivativesuch as acetate ester, nicotinate ester or succinate ester in manycases. In order to allow the organic acid ester derivative to exert invivo the physiological activity as tocopherol, the ester bond moietymust be hydrolyzed by an enzyme such as esterase, however, theconversion rate of those derivatives is not sufficiently high and theeffect of increasing the concentration in the tissue is low.

It is an object of the present invention to improve the solubility andemulsifiability of tocopherol in skin preparations for externalapplication and provide a composition which undergoes efficientconversion to active tocopherol in the skin tissue.

DISCLOSURE OF THE INVENTION

As a result of extensive investigations to overcome the above-describedproblems, the present inventors have found that a tocopherolaminoalkylcarboxylate ester having a substituent on the N atom and/or asalt thereof have useful solubility and emulsifiability, and haveaccomplished the present invention. As used herein, “having asubstituent on the N atom” means to have a substituent other than analkylcarboxylate group on an amino group of the aminoalkylcarboxylate.

The present inventors have also found that the tocopherolaminoalkylcarboxylate ester having a substituent on the N atom and/or asalt thereof are efficiently converted to active tocopherol in skintissue, and have accomplished the present invention.

More specifically, the present invention relates to the followingmatters.

[1] A skin preparation for external application, comprising a tocopherolaminoalkylcarboxylate ester having a substituent on the N atom and/or asalt thereof.

[2] The skin preparation for external application as described in [1]above, wherein the tocopherol aminoalkylcarboxylate ester is one or morecompound selected from α-tocopherol derivatives, β-tocopherolderivatives, γ-tocopherol derivatives and δ-tocopherol derivatives.

[3] The skin preparation for external application as described in [2]above, wherein the tocopherol amino-alkylcarboxylate ester is anα-tocopherol aminoalkylcarboxylate ester or a γ-tocopherolaminoalkylcarboxylate ester.

[4] The skin preparation for external application as described in anyone of [1] to [3] above, wherein the tocopherol aminoalkylcarboxylateester having a substituent on the N atom comprises a compoundrepresented by formula (I):

(wherein R¹ and R² may be the same or different and each represents alower alkyl group or a hydrogen atom, R³and R⁴ each represents ahydrogen atom or a methyl group and R represents a branched or linearalkylene group which may have a substituent, provided that R¹ and R² arenot a hydrogen atom at the same time).

[5] The skin preparation for external application as described in anyone of [1] to [4] above, wherein the tocopherol aminoalkylcarboxylateester having a substituent on the N atom comprises a compoundrepresented by formula (II):

(wherein R¹ and R² may be the same or different and each represents alower alkyl group or a hydrogen tom, R³ and R⁴ each represents ahydrogen atom or a methyl group, and n represents an integer of 1 to 7,provided that R¹ and R² are not a hydrogen atom at the same time).

[6] The skin preparation for external application as described in anyone of [1] to [5] above, wherein the aminoalkylcarboxylic acid of thetocopherol aminoalkylcarboxylate ester having a substituent on the Natom is a compound selected from the group consisting of glycine,alanine, β-alanine, valine, leucine, isoleucine, phenylalanine,methionine, cysteine, serine, threonine, tyrosine, thyroxine, histidine,proline, 4-hydroxyproline, aspartic acid, glutamic acid and theirN-alkyl derivatives and N,N-dialkyl derivatives.

[7] The skin preparation for external application as described in anyone of [1] to [6] above, wherein the aminoalkylcarboxylic acid of thetocopherol aminoalkylcarboxylate ester having a substituent on the Natom has a monoamino group and the monoamino groiup is a monoalkylaminogroup.

[8] The skin preparation for external application as described in anyone of [1] to [7] above, wherein the aminoalkylcarboxylic acid of thetocopherol aminoalkylcarboxylate ester having a substituent on the Natom has a monoamino group and the monoamino group is a dialkylaminogroup.

[9] The skin preparation for external application as described in [7]above, wherein the tocopherol aminoalkylcarboxylate ester having asubstituent on the N atom is an N,N-dimethylglycine ester of tocopherol.

[10] The skin preparation for external application as described in [8]above, wherein the tocopherol aminoalkylcarboxylate ester having asubstituent on the N atom is a tocopherol sarcosine ester.

[11] The skin preparation for external application as described in anyone of [1] to [10] above, wherein the salt is a hydrohalogenic acidsalt.

[12] The skin preparation for external application as described in [11]above, wherein the hydrohalogenic acid is hydrochloric acid.

[13] The skin preparation for external application as described in anyone of [1] to [12] above, wherein the content of the tocopherolaminoalkylcarboxylate ester having a substituent on the N atom and/or asalt thereof is from 0.01 to 10 mass %.

[14] A cosmetic material comprising the skin preparation for externalapplication described in any one of [1] to [13] above.

BEST MODE FOR CARRYING OUT THE INVENTION

The tocopherol aminoalkylcarboxylate ester derivative having asubstituent on the N atom and/or a salt thereof for use in the skinpreparation for external application of the present invention aredescribed below.

In the present invention, the tocopherol aminoalkylcarboxylate esterhaving a substituent on the N atom is, for example, a compoundrepresented by the following formula (I) and/or a salt thereof:

(wherein R¹ and R² may be the same or different and each represents alower alkyl group or a hydrogen atom, R³ and R⁴ each represents ahydrogen atom or a methyl group and R represents a branched or linearalkylene group which may have a substituent, provided that R¹ and R² arenot a hydrogen atom at the same time).

As seen from the formula above, the tocopherol which can be used in thepresent invention includes α-, β-, γ- and δ-tocopherol derivatives.Among these, preferred are α-tocopherol where R³ and R⁴ are methyl, andγ-tocopherol where R³ is methyl and R⁴ is a hydrogen atom.

These tocopherol derivatives have an asymmetric carbon atom at the2-position of the chromanol ring and therefore, steric isomers such as dform and dl form are present. Needless to say, the present inventionincludes all of these isomers.

The lower alkyl group in the definition of R¹ and R² of formula (I) is alinear or branched alkyl group having from 1 to 6 carbon atoms andexamples thereof include methyl, ethyl, n-propyl, n-butyl, isopropyl,isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyland n-hexyl. Among these, most preferred are a methyl group and an ethylgroup.

Examples of the aminoalkylcarboxylic acids constituting the tocopherolaminoalkylcarboxylate ester for use in the present invention includeglycine, alanine, βalanine, valine, leucine, isoleucine, phenylalanine,methionine, cysteine, serine, threonine, tyrosine, thyroxine, histidine,proline, 4-hydroxyproline, aspartic acid, glutamic acid and theirN-alkyl derivatives and N,N-dialkyl derivatives.

Among these aminoalkylcarboxylic acids, preferred are dimethylglycineand sarcosine.

These aminoalkylcarboxylic acids may be any of D form, L form and DLform but in view of bioactivity and the like, L form or DL form ispreferred.

In the present invention, a salt is preferred and the salt is preferablya hydrohalogenic acid salt, more preferably an HCl salt or an HBr salt.In particular, the HCl salt is advantageous in that the solubility inwater increases and due to its powder form, handling is facilitated.

The tocopherol aminoalkylcarboxylate ester derivative having asubstituent on the N atom for use in the present invention may beproduced by various methods, but a representative method is describedbelow.

The production method is described by referring to the case ofR═(CH₂)_(n) (wherein n represents an integer of 1 to 7) which is apreferred example.

This compound can be easily obtained by performing an esterificationreaction of a tocopherol represented by the following formula (III):

(wherein R³ and R⁴ each represents a hydrogen atom or a methyl group)and any one of an aminoalkylcarboxylic acid represented by the followingformula (IV):

(wherein R¹ and R² may be the same or different and each represents alower alkyl group or a hydrogen atom, and R represents a branched orlinear alkylene group which may have a substituent, provided that R¹ andR² are not a hydrogen atom at the same time), its reactive acidderivative and a salt thereof such as hydrohalogenic acid salt, in ausual manner.

In the case of directly performing the esterification using a freeaminoalkylcarboxylic acid, usually, the reaction is preferably performedin the presence of an active esterification reagent (dehydrating agent)such as dicyclohexylcarbodiimide and N,N-disuccinimide oxalate. At thistime, the solvent is most preferably pyridine.

If desired, the aminoalkylcarboxylic acid having a substituent on the Natom after the completion of reaction is preferably subjected to atreatment for removing the protective group using anaminoalkylcarboxylic acid in which the amino group is protected, forexample, by an N-tert-butoxycarbonyl (BOC) group, a benzyloxycarbonylgroup or a 2-nitrobenzenesulfonyl group.

In the method of using a reactive acid derivative, an acid halide,particularly acid chloride is preferably used.

In the case of producing a hydrohalogenic acid salt of a tocopherolaminoalkylcarboxylate ester, the hydrohalogenic acid salt may beproduced by once producing an ester form and reacting it with ahydrohalogenic acid (gas phase or solution) in a usual manner, or ahydrohalogenic acid salt of an aminoalkylcarboxylic acid represented byformula (IV) may be previously used as a starting material.

The thus-obtained tocopherol aminoalkylcarboxylate ester having asubstituent on the N atom and/or a hydrohalogenic acid salt thereof areexcellent in the solubility and emulsifiability as compared withtocopherols in a simple form. Furthermore, when applied as a skinpreparation for external application, these are readily hydrolyzed by anesterase or carboxyl esterase in the skin tissue to produce an activefree tocopherol.

Therefore, the tocopherol aminoalkylcarboxylate ester having asubstituent on the N atom and/or a hydrohalogenic acid salt thereof ofthe present invention can be used as an active ingredient of skinpreparations for external application which are expected to haveefficacy and effect such as activities of antioxidation, vital membranestabilization, immunoactivation and acceleration of blood circulation.

The present invention relates to a skin preparation for externalapplication where a tocopherol aminoalkylcarboxylate ester having asubstituent on the N atom and/or a hydrohalogenic acid salt thereof isblended, and the skin preparation for external application of thepresent invention can be used as a cosmetic material.

The cosmetic material of the present invention includes, in a widesense, cosmetic materials which come into contact with skin on use, forexample, skin milk, skin cream, foundation cream, massage cream,cleansing cream, shaving cream, cleansing foam, skin lotion, lotion,pack, shampoo, rinse, hair restorer, hair nourishment, hair dye, hairconditioner, toothpaste, gargle, permanent waving agent, ointment, bathpreparation and body soap. The user may be any user irrespective of sexor age.

In the skin preparation for external application and the cosmeticmaterial of the present invention, ingredients commonly used in skinpreparations for external application can be blended within the range ofnot impairing the effect of the present invention. Examples thereofinclude chemicals described in Japanese Standards of CosmeticIngredients (JSCI), 2nd Edition, Annotation, compiled by Nippon KoteishoKyokai, issued by Yakuji Nippo, Ltd. (1984), Specifications ofIngredient Other Than Those Listed in JSCI, supervised by ExaminationDivision, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare,issued by Yakuji Nippo, Ltd. (1993), Specifications of Ingredient OtherThan Those Listed in JSCI, Supplement, supervised by ExaminationDivision, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare,issued by Yakuji Nippo, Ltd. (1993), The Comprehensive LicensingStandards of Cosmetics by Category, supervised by Examination Division,Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, issued byYakuji Nippo, Ltd. (1993), and Kesho-hin Genryo Jiten (Handbook ofCosmetic Ingredients), Nikko Chemicals (1991).

EXAMPLES

The present invention is described in greater detail below by referringto Examples, however, the present invention is not limited to theseExamples. In Examples, the amount blended is in the unit of mass %.

Example 1

Lotion 1 Example 1 1) α-Tocopherol dimethylglycine ester 2.00hydrochloride 2) Ethanol 5.00 3) Propylene glycol 5.00 4) Methylparahydroxybenzoate 0.20 5) Purified water 87.8

(Production Method of Example 1)

Ingredients 1) and 2) to 4) were uniformly dispersed and dissolved andthe resulting solution was added to 5) with stirring to obtain theobjective lotion.

Example 2

Lotion 2 Example 2 1) α-Tocopherol sarcosine ester 2.00 hydrochloride 2)Ethanol 5.00 3) Propylene glycol 5.00 4) Methyl parahydroxybenzoate 0.205) Purified water 87.8

(Production Method of Example 2)

Ingredients 1) and 2) to 4) were uniformly dispersed and dissolved andthe resulting solution was added to 5) with stirring to obtain theobjective lotion.

Comparative Example 1

Lotion 3 Comparative Example 1 1) Tocopherol acetate 2.00 2) Ethanol5.00 3) Propylene glycol 5.00 4) Methyl parahydroxybenzoate 0.20 5)Purified water 87.8

(Production Method of Comparative Example 1)

Ingredients 1) to 4) were uniformly dispersed and dissolved and theresulting solution was added to 5) with stirring to obtain the objectivelotion.

(Results)

Lotion 1 obtained in Examples 1 and 2 was uniformly dissolved andexhibited good aging stability. On the other hand, in ComparativeExample 1, uniform dissolution or dispersion could not be attained and alotion having excellent solubility could not be obtained.

Example 3

Lotion 4 Example 3 1) α-Tocopherol dimethylglycine ester 0.10hydrochloride 2) Propylene glycol 5.00 3) Methyl parahydroxybenzoate0.20 4) Purified water 94.7

(Production Method of Example 3)

Ingredients 1), 2) and 3) were uniformly dispersed and dissolved and theresulting solution was added to 4) with stirring to obtain the objectivelotion.

Example 4

Lotion 5 Example 4 1) α-Tocopherol sarcosine ester 0.10 hydrochloride 2)Propylene glycol 5.00 3) Methyl parahydroxybenzoate 0.20 4) Purifiedwater 94.7

(Production Method of Example 4)

Ingredients 1), 2) and 3) were uniformly dispersed and dissolved and theresulting solution was added to 4) with stirring to obtain the objectivelotion.

Comparative Example 2

Lotion 6 Comparative Example 2 1) Tocopherol acetate 0.10 2) Propyleneglycol 5.00 3) Methyl parahydroxybenzoate 0.20 4) Purified water 94.7

(Production Method of Comparative Example 2)

Ingredients 1), 2) and 3) were uniformly dispersed and dissolved and theresulting solution was added to 4) with stirring to obtain the objectivelotion.

(Results)

Lotions 4 and 5 obtained in Examples 3 and 4 were uniformly dissolvedand exhibited good aging stability. On the other hand, in ComparativeExample 2, uniform dissolution or dispersion could not be attained,floating of oil droplets was confirmed and a lotion 6 having excellentsolubility could not be obtained.

Example 5

Lotion 7 Example 5 1) α-Tocopherol dimethylglycine ester 0.10hydrochloride 2) Propylene glycol 5.00 3) Methyl parahydroxybenzoate0.20 4) Sodium ascorbyl phosphate 3.00 5) Purified water 91.7

(Production Method of Example 5)

Ingredients 1), 2) and 3) were uniformly dispersed and dissolved and theresulting solution was added with stirring to 5) in which 4) waspreviously dissolved, to obtain the objective lotion.

Example 6

Lotion 8 Example 6 1) α-Tocopherol sarcosine ester 0.10 hydrochloride 2)Propylene glycol 5.00 3) Methyl parahydroxybenzoate 0.20 4) Magnesiumascorbyl phosphate 3.00 5) Purified water 91.7

(Production Method of Example 6)

Ingredients 1), 2) and 3) were uniformly dispersed and dissolved and theresulting solution was added with stirring to 5) in which 4) waspreviously dissolved, to obtain the objective lotion.

Comparative Example 3

Lotion 9 Comparative Example 3 1) Tocopherol acetate 0.10 2) Propyleneglycol 5.00 3) Methyl parahydroxybenzoate 0.20 4) Sodium ascorbylphosphate 3.00 5) Purified water 91.7

(Production Method of Comparative Example 3)

Ingredients 1), 2) and 3) were uniformly dispersed and dissolved and theresulting solution was added with stirring to 5) in which 4) waspreviously dissolved, to obtain the objective lotion.

(Results)

Lotions 7 and 8 obtained in Examples 5 and 6 were uniformly dissolvedand exhibited good aging stability. On the other hand, in ComparativeExample 3, uniform dissolution or dispersion could not be attained,floating of oil droplets was confirmed and a lotion having excellentsolubility could not be obtained.

Example 7

Gel Preparation 1 for External Application Example 7 1) α-Tocopheroldimethylglycine ester 10.0 hydrochloride 2) Glycerin 20.0 3)Octyldodecyl myristate 70.0

(Production Method of Example 7)

Ingredient 1) was uniformly dispersed in 2) and the resulting dispersionwas added to 3) with stirring to obtain the objective gel preparation 1for external application.

Example 8

Gel Preparation 2 for External Application Example 8 1) α-Tocopherolsarcosine ester 10.0 hydrochloride 2) Glycerin 20.0 3) Octyldodecylmyristate 70.0

(Production Method of Example 8)

Ingredient 1) was uniformly dispersed in 2) and the resulting dispersionwas added to 3) with stirring to obtain the objective gel preparation 2for external application.

Comparative Example 4

Gel Preparation 3 for External Application Comparative Example 4 1)Tocopherol acetate 10.0 2) Glycerin 20.0 3) Octyldodecyl myristate 70.0

(Production Method of Comparative Example 4)

Ingredient 1) was uniformly dispersed in 2) and the resulting dispersionwas added to 3) with stirring to obtain the objective gel preparation 3for external application.

(Results)

Gel preparations 1 and 2 for external application obtained in Examples 7and 8 had a translucent gel appearance and exhibited good agingstability. On the other hand, in Comparative Example 4, gel was notformed.

Example 9

Milky Lotion 1 Example 9 1) α-Tocopherol dimethylglycine ester 5.0hydrochloride 2) Propylene glycol 10.0 3) Methyl parahydroxybenzoate0.20 4) Methylphenylpolysiloxane 20.0 5) Purified water 64.8

(Production Method of Example 9)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added to 5) with stirring to obtain the objective milky lotion 1.

Example 10

Milky Lotion 2 Example 10 1) α-Tocopherol sarcosine ester 5.0hydrochloride 2) Propylene glycol 10.0 3) Methyl parahydroxybenzoate0.20 4) Methylphenylpolysiloxane 20.0 5) Purified water 64.8

(Production Method of Example 10)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added to 5) with stirring to obtain the objective milky lotion 2.

Comparative Example 5

Milky Lotion 3 Comparative Example 5 1) Tocopherol acetate 5.00 2)Propylene glycol 10.0 3) Methyl parahydroxybenzoate 0.20 4)Methylphenylpolysiloxane 20.0 5) Purified water 64.8

(Production Method of Comparative Example 5)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added to 5) with stirring to obtain the objective milky lotion 3.

(Results)

Milky lotions 1 and 2 obtained in Examples 9 and 10 gave good feeling onuse and exhibited good aging stability. On the other hand, inComparative Example 5, emulsion was not formed and a milky lotion couldnot be obtained.

Example 11

Milky Lotion 4 Example 11 1) α-Tocopherol dimethylglycine ester 5.00hydrochloride 2) Propylene glycol 10.0 3) Methyl parahydroxybenzoate0.20 4) Methylphenylpolysiloxane 20.0 5) Sodium ascorbyl phosphate 3.006) Purified water 61.8

(Production Method of Example 11)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added, with stirring, to 6) in which 5) was previously dissolved toobtain the objective milky lotion 4.

Example 12

Milky Lotion 5 Example 12 1) α-Tocopherol dimethylglycine ester 5.0hydrochloride 2) Propylene glycol 10.0 3) Methyl parahydroxybenzoate0.20 4) Methylphenylpolysiloxane 20.0 5) Magnesium ascorbyl phosphate3.00 6) Purified water 61.8

(Production Method of Example 12)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added, with stirring, to 6) in which 5) was previously dissolved toobtain the objective milky lotion 5.

Example 13

Milky Lotion 6 Example 13 1) α-Tocopherol sarcosine ester 5.00hydrochloride 2) Propylene glycol 10.0 3) Methyl parahydroxybenzoate0.20 4) Methylphenylpolysiloxane 20.0 5) Sodium ascorbyl phosphate 3.006) Purified water 61.8

(Production Method of Example 13)

Any one of 1) to 3) was uniformly dispersed and dissolved in 5) to 6)and thereto, 9) in which 8) was previously dissolved was added withstirring to obtain the objective milky lotion 6.

Example 14

Milky Lotion 7 Example 14 1) α-Tocopherol sarcosine ester 5.00hydrochloride 2) Propylene glycol 10.0 3) Methyl parahydroxybenzoate0.20 4) Methylphenylpolysiloxane 20.0 5) Magnesium ascorbyl phosphate3.00 6) Purified water 61.8

(Production Method of Example 14)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added, with stirring, to 6) in which 5) was previously dissolved toobtain the objective milky lotion 7.

Comparative Example 6

Milky Lotion 8 Comparative Example 6 1) Tocopherol acetate 5.00 2)Propylene glycol 10.0 3) Methyl parahydroxybenzoate 0.20 4)Methylphenylpolysiloxane 20.0 5) Sodium ascorbyl phosphate 3.00 6)Purified water 61.8

(Production Method of Comparative Example 6)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and theresulting solution was added with stirring to 6) in which 5) waspreviously dissolved, to obtain the objective milky lotion 8.

(Results)

Milky lotions 4 to 7 obtained in Examples 11 to 14 gave good feeling onuse and exhibited good aging stability. On the other hand, inComparative Example 6, emulsion was not formed and a milky lotion couldnot be obtained.

Example 15

Milky Lotion 9 Example 15 1) α-Tocopherol dimethylglycine ester 5.00hydrochloride 2) Hydrogenated soybean phospholipid 10.0 3) Methylparahydroxybenzoate 0.20 4) 2-Ethylhexanoic acid triglyceride 20.0 5)Sodium ascorbyl phosphate 2.00 6) Purified water 61.8

(Production Method of Example 15)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added, with stirring, to 6) in which 5) was previously dissolved toobtain the objective milky lotion 9.

Example 16

Milky Lotion 10 Example 16 1) α-Tocopherol dimethylglycine ester 5.00hydrochloride 2) Hydrogenated soybean phospholipid 10.0 3) Methylparahydroxybenzoate 0.20 4) 2-Ethylhexanoic acid triglyceride 20.0 5)Magnesium ascorbyl phosphate 2.00 6) Purified water 61.8

(Production Method of Example 16)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added, with stirring, to 6) in which 5) was previously dissolved toobtain the objective milky lotion 10.

Example 17

Milky Lotion 11 Example 17 1) α-Tocopherol sarcosine ester 5.00hydrochloride 2) Hydrogenated soybean phospholipid 10.0 3) Methylparahydroxybenzoate 0.20 4) 2-Ethylhexanoic acid triglyceride 20.0 5)Sodium ascorbyl phosphate 2.00 6) Purified water 61.8

(Production Method of Example 17)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added to 6) in which 5) was previously dissolved with stirring toobtain the objective milky lotion 11.

Example 18

Milky Lotion 12 Example 18 1) α-Tocopherol sarcosine ester 5.00hydrochloride 2) Hydrogenated soybean phospholipid 10.0 3) Methylparahydroxybenzoate 0.20 4) 2-Ethylhexanoic acid triglyceride 20.0 5)Magnesium ascorbyl phosphate 2.00 6) Purified water 61.8

(Production Method of Example 17)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added, with stirring, to 6) in which 5) was previously dissolved toobtain the objective milky lotion 12.

Comparative Example 7

Milky Lotion 13 Comparative Example 7 1) Tocopherol acetate 5.00 2)Hydrogenated soybean phospholipid 10.0 3) Methyl parahydroxybenzoate0.20 4) 2-Ethylhexanoic acid triglyceride 20.0 5) Sodium ascorbylphosphate 2.00 6) Purified water 61.8

(Production Method of Comparative Example 7)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and theresulting solution was added with stirring to 6) in which 5) waspreviously dissolved, to obtain the objective milky lotion 13.

(Results)

Milky lotions 9 to 12 obtained in Examples 15 to 18 gave good feeling onuse and exhibited good aging stability. On the other hand, in the milkylotion 13 obtained in Comparative Example 7, phase separation wasobserved after a few days and good aging stability could not beobtained.

Example 19 and Comparative Example 8

Evaluation of Skin Penetrability

(Method)

In each of φ+35 mm plastic Petri dishes, 1 ml of a Dulbecco's MEM mediumcontaining 1), 2), 3) or 4) was placed and a nylon mesh and a lens paperwere sequentially laid thereon. On the lens paper, a skin removed fromthe back of a hairless mouse was placed such that the epidermis cameinto contact with the lens paper. At this time, the dermis side wascovered with a parafilm and thereby prevented from drying. 1) Not added2) α-Tocopherol dimethylglycine 0.50 ester hydrochloride 3) α-Tocopherolsarcosine 0.50 ester hydrochloride 4) Tocopherol acetate 0.50

After the passage of 4 hours at 37° C., the skin was washed with aphosphoric acid buffer solution and homogenized. Then, the amount ofα-tocopherol in the skin was measured. The determination of α-tocopherolwas performed by high performance liquid chromatography.

The conditions for measurement by high performance liquid chromatographywere as follows.

-   -   Column: Shodex ODSpak F-411    -   Temperature: 40° C.    -   Eluent: methanol/acetonitrile=7/3 (containing 0.02M acetic acid        and 0.02M sodium acetate)    -   Flow rate: 0.7 ml    -   Detection: fluorescent, Ex: 298 nm, Em: 325 nm        (Results)    -   1) 10 nmol/g of skin    -   2) 17 nmol/g of skin    -   3) 20 nmol/g of skin    -   4) 11 nmol/g of skin

The skin treated with α-tocopherol dimethylglycine ester hydrochlorideor α-tocopherol sarcosine ester hydrochloride had significant increaseof the α-tocopherol amount.

Example 20 and Comparative Example 9

Conversion to α-Tocopherol in Keratinocyte of Human Epidermis

(Method)

Commercially available keratinocytes of normal human epidermis werecultured in the medium attached. The cells were harvested and spalled byfreeze-thawing method. To this cell spall solution, 1), 2), 3) or 4) wasadded to have a final concentration of 1 mM. The resulting solution waskept at 37° C. for 2 hours and then the amount of α-tocopherol liberatedin the reaction solution was measured. The determination of α-tocopherolwas performed by high performance liquid chromatography.

The conditions for measurement by high performance liquid chromatographywere as follows.

-   -   Column: Shodex ODSpak F-411    -   Temperature: 40° C.    -   Eluent: methanol/acetonitrile=7/3 (containing 0.02M acetic acid        and 0.02M sodium acetate)    -   Flow rate: 0.7 ml    -   Detection: fluorescent, Ex: 298 nm, Em: 325 nm

-   1) Not added

-   2) α-Tocopherol dimethylglycine ester hydrochloride

-   3) α-Tocopherol sarcosine ester hydrochloride

-   4) Tocopherol acetate    (Results)    -   1) lower than detection limit    -   2) 6.9 nmol/ml of cell suspension    -   3) 26.9 nmol/ml of cell suspension    -   4) 0.5 nmol/ml of cell suspension

The cell spall solution in which α-tocopherol dimethylglycine esterhydrochloride or α-tocopherol sarcosine ester hydrochloride was added,had significant increase of the α-tocopherol amount.

Example 21

Lotion 10 Example 21 1) γ-Tocopherol dimethylglycine ester 2.00hydrochloride 2) Ethanol 5.00 3) Propylene glycol 5.00 4) Methylparahydroxybenzoate 0.20 5) Purified water 87.8

(Production Method of Example 21)

Ingredients 1) and 2) to 4) were uniformly dispersed and dissolved andthe resulting solution was added to 5) with stirring to obtain theobjective lotion 10.

Example 22

Lotion 11 Example 22 1) γ-Tocopherol sarcosine ester 2.00 hydrochloride2) Ethanol 5.00 3) Propylene glycol 5.00 4) Methyl parahydroxybenzoate0.20 5) Purified water 87.8

(Production Method of Example 22)

Ingredients 1) and 2) to 4) were uniformly dispersed and dissolved andthe resulting solution was added to 5) with stirring to obtain theobjective lotion 11.

Comparative Example 10

Lotion 12 Comparative Example 10 1) γ-Tocopherol 2.00 2) Ethanol 5.00 3)Propylene glycol 5.00 4) Methyl parahydroxybenzoate 0.20 5) Purifiedwater 87.8

(Production Method of Comparative Example 10)

Ingredients 1) and 2) to 4) were uniformly dispersed and dissolved andthe resulting solution was added to 5) with stirring to obtain theobjective lotion 12.

(Results)

Lotions 10 and 11 obtained in Examples 21 and 22 was uniformly dissolvedand exhibited good aging stability. On the other hand, in ComparativeExample 10, uniform dissolution or dispersion could not be attained anda lotion having excellent solubility could not be obtained.

Example 23

Lotion 13 Example 23 1) γ-Tocopherol dimethylglycine ester 0.10hydrochloride 2) Propylene glycol 5.00 3) Methyl parahydroxybenzoate0.20 4) Purified water 94.7

(Production Method of Example 23)

Ingredients 1), 2) and 3) were uniformly dispersed and dissolved and theresulting solution was added to 4) with stirring to obtain the objectivelotion 13.

Example 24

Lotion 14 Example 24 1) γ-Tocopherol sarcosine ester 0.10 hydrochloride2) Propylene glycol 5.00 3) Methyl parahydroxybenzoate 0.20 4) Purifiedwater 94.7

(Production Method of Example 23)

Ingredients 1), 2) and 3) were uniformly dispersed and dissolved and theresulting solution was added to 4) with stirring to obtain the objectivelotion 14.

Comparative Example 11

Lotion 15 Comparative Example 11 1) γ-Tocopherol 0.10 2) Propyleneglycol 5.00 3) Methyl parahydroxybenzoate 0.20 4) Purified water 94.7

(Production Method of Comparative Example 11)

Ingredients 1), 2) and 3) were uniformly dispersed and dissolved and theresulting solution was added to 4) with stirring to obtain the objectivelotion 15.

(Results)

Lotions 13 and 14 obtained in Examples 23 and 24 were uniformlydissolved and exhibited good aging stability. On the other hand, inComparative Example 11, uniform dissolution or dispersion could not beattained, floating of oil droplets was confirmed and a lotion havingexcellent solubility could not be obtained.

Example 25

Lotion 16 Example 25 1) γ-Tocopherol dimethylglycine ester 0.10hydrochloride 2) Propylene glycol 5.00 3) Methyl parahydroxybenzoate0.20 4) Sodium ascorbyl phosphate 3.00 5) Purified water 91.7

Ingredients 1), 2) and 3) were uniformly dispersed and dissolved and theresulting solution was added with stirring to 5) in which 4) waspreviously dissolved, to obtain the objective lotion 16.

Example 26

Lotion 17 Example 26 1) γ-Tocopherol dimethylglycine ester 0.10hydrochloride 2) Propylene glycol 5.00 3) Methyl parahydroxybenzoate0.20 4) Magnesium ascorbyl phosphate 3.00 5) Purified water 91.7

(Production Method of Example 26)

Ingredients 1), 2) and 3) were uniformly dispersed and dissolved and theresulting solution was added with stirring to 5) in which 4) waspreviously dissolved, to obtain the objective lotion 17.

Example 27

Lotion 18 Example 27 1) γ-Tocopherol sarcosine ester 0.10 hydrochloride2) Propylene glycol 5.00 3) Methyl parahydroxybenzoate 0.20 4) Sodiumascorbyl phosphate 3.00 5) Purified water 91.7

(Production Method of Example 27)

Ingredients 1), 2) and 3) were uniformly dispersed and dissolved and theresulting solution was added with stirring to 5) in which 4) waspreviously dissolved, to obtain the objective lotion 18.

Example 28

Lotion 19 Example 28 1) γ-Tocopherol sarcosine ester 0.10 hydrochloride2) Propylene glycol 5.00 3) Methyl parahydroxybenzoate 0.20 4) Magnesiumascorbyl phosphate 3.00 5) Purified water 91.7

(Production Method of Example 28)

Ingredients 1), 2) and 3) were uniformly dispersed and dissolved and theresulting solution was added with stirring to 5) in which 4) waspreviously dissolved, to obtain the objective lotion 19.

Comparative Example 12

Lotion 20 Comparative Example 12 1) γ-Tocopherol 0.10 2) Propyleneglycol 5.00 3) Methyl parahydroxybenzoate 0.20 4) Sodium ascorbylphosphate 3.00 5) Purified water 91.7

(Production Method of Comparative Example 12)

Ingredients 1), 2) and 3) were uniformly dispersed and dissolved and theresulting solution was added with stirring to 5) in which 4) waspreviously dissolved, to obtain the objective lotion 20.

(Results)

Lotions 16 to 19 obtained in Examples 25 to 28 were uniformly dissolvedand exhibited good aging stability. On the other hand, in ComparativeExample 12, uniform dissolution or dispersion could not be attained,floating of oil droplets was confirmed and a lotion having excellentsolubility could not be obtained.

Example 29

Gel Preparation 4 for External Application Example 29 1) γ-Tocopheroldimethylglycine ester 10.0 hydrochloride 2) Glycerin 20.0 3)Octyldodecyl myristate 70.0

(Production Method of Example 28)

Ingredient 1) was uniformly dispersed in 2) and the resulting dispersionwas added to 3) with stirring to obtain the objective gel preparation 4for external application.

Example 30

Gel Preparation 5 for External Application Example 30 1) γ-Tocopherolsarcosine ester 10.0 hydrochloride 2) Glycerin 20.0 3) Octyldodecylmyristate 70.0

(Production Method of Example 30)

Ingredient 1) was uniformly dispersed in 2) and the resulting dispersionwas added to 3) with stirring to obtain the objective gel preparation 5for external application.

Comparative Example 13

Gel Preparation 6 for External Application Comparative Example 13 1)γ-Tocopherol 10.0 2) Glycerin 20.0 3) Octyldodecyl myristate 70.0

(Production Method of Comparative Example 13)

Ingredient 1) was uniformly dispersed in 2) and the resulting dispersionwas added to 3) with stirring to obtain the objective gel preparationfor external application.

(Results)

Gel preparations 4 and 5 for external application obtained in Examples29 and 30 had a translucent gel appearance and exhibited good agingstability. On the other hand, in Comparative Example 13, gel was notformed.

Example 31

Milky Lotion 14 Example 31 1) γ-Tocopherol dimethylglycine ester 5.00hydrochloride 2) Propylene glycol 10.0 3) Methyl parahydroxybenzoate0.20 4) Methylphenylpolysiloxane 20.0 5) Purified water 64.8

(Production Method of Example 31)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added to 5) with stirring to obtain the objective milky lotion 14.

Example 32

Milky Lotion 15 Example 32 1) γ-Tocopherol sarcosine ester 5.0hydrochloride 2) Propylene glycol 10.0 3) Methyl parahydroxybenzoate0.20 4) Methylphenylpolysiloxane 20.0 5) Purified water 64.8

(Production Method of Example 32)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added to 5) was added with stirring to obtain the objective milkylotion 15.

Comparative Example 14

Milky Lotion 16 Comparative Example 14 1) γ-Tocopherol 5.00 2) Propyleneglycol 10.0 3) Methyl parahydroxybenzoate 0.20 4)Methylphenylpolysiloxane 20.0 5) Purified water 64.8

(Production Method of Comparative Example 14)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added to 5) was added with stirring to obtain the objective milkylotion 16.

(Results)

Milky lotions 14 and 15 obtained in Examples 31 and 32 gave good feelingon use and exhibited good aging stability. On the other hand, inComparative Example 14, emulsion was not formed and a milky lotion couldnot be obtained.

Example 33

Milky Lotion 17 Example 33 1) γ-Tocopherol dimethylglycine ester 5.00hydrochloride 2) Propylene glycol 10.0 3) Methyl parahydroxybenzoate0.20 4) Methylphenylpolysiloxane 20.0 5) Sodium ascorbyl phosphate 3.006) Purified water 61.8

(Production Method of Example 33)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added, with stirring, to 6) in which 5) was previously dissolved toobtain the objective milky lotion 17.

Example 34

Milky Lotion 18 Example 34 1) γ-Tocopherol dimethylglycine ester 5.00hydrochloride 2) Propylene glycol 10.0 3) Methyl parahydroxybenzoate0.20 4) Methylphenylpolysiloxane 20.0 5) Magnesium ascorbyl phosphate3.00 6) Purified water 61.8

(Production Method of Example 34)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added, with stirring, to 6) in which 5) was previously dissolved toobtain the objective milky lotion 18.

Example 35

Milky Lotion 19 Example 35 1) γ-Tocopherol sarcosine ester 5.00hydrochloride 2) Propylene glycol 10.0 3) Methyl parahydroxybenzoate0.20 4) Methylphenylpolysiloxane 20.0 5) Sodium ascorbyl phosphate 3.006) Purified water 61.8

(Production Method of Example 35)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added, with stirring, to 6) in which 5) was previously dissolved toobtain the objective milky lotion 19.

Example 36

Milky Lotion 20 Example 36 1) γ-Tocopherol sarcosine ester 5.00hydrochloride 2) Propylene glycol 10.0 3) Methyl parahydroxybenzoate0.20 4) Methylphenylpolysiloxane 20.0 5) Magnesium ascorbyl phosphate3.00 6) Purified water 61.8

(Production Method of Example 36)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added, with stirring, to 6) in which 5) was previously dissolved toobtain the objective milky lotion 20.

Comparative Example 15

Milky Lotion 21 Comparative Example 15 1) γ-Tocopherol 5.00 2) Propyleneglycol 10.0 3) Methyl parahydroxybenzoate 0.20 4)Methylphenylpolysiloxane 20.0 5) Sodium ascorbyl phosphate 3.00 6)Purified water 61.8

(Production Method of Comparative Example 15)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and thiswas added, with stirring, to 6) in which 5) was previously dissolved toobtain the objective milky lotion 21.

(Results)

Milky lotions 17 to 20 obtained in Examples 33 to 36 gave good feelingon use and exhibited good aging stability. On the other hand, inComparative Example 15, emulsion was not formed and a milky lotion couldnot be obtained.

Example 37

Milky Lotion 22 Example 37 1) γ-Tocopherol dimethylglycine ester 5.00hydrochloride 2) Hydrogenated soybean phospholipid 10.0 3) Methylparahydroxybenzoate 0.20 4) 2-Ethylhexanoic acid triglyceride 20.0 5)Sodium ascorbyl phosphate 2.00 6) Purified water 61.8

(Production Method of Example 37)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and theresulting solution was added with stirring to 6) in which 5) waspreviously dissolved, to obtain the objective milky lotion 22.

Example 38

Milky Lotion 23 Example 38 1) γ-Tocopherol dimethylglycine ester 5.00hydrochloride 2) Hydrogenated soybean phospholipid 10.0 3) Methylparahydroxybenzoate 0.20 4) 2-Ethylhexanoic acid triglyceride 20.0 5)Magnesium ascorbyl phosphate 2.00 6) Purified water 61.8

(Production Method of Example 38)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and theresulting solution was added with stirring to 6) in which 5) waspreviously dissolved, to obtain the objective milky lotion 23.

Example 39

Milky Lotion 24 Example 39 1) γ-Tocopherol sarcosine ester 5.00hydrochloride 2) Hydrogenated soybean phospholipid 10.0 3) Methylparahydroxybenzoate 0.20 4) 2-Ethylhexanoic acid triglyceride 20.0 5)Sodium ascorbyl phosphate 2.00 6) Purified water 61.8

(Production Method of Example 39)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and theresulting solution was added with stirring to 6) in which 5) waspreviously dissolved, to obtain the objective milky lotion 24.

Example 40

Milky Lotion 25 Example 40 1) γ-Tocopherol sarcosine ester 5.00hydrochloride 2) Hydrogenated soybean phospholipid 10.0 3) Methylparahydroxybenzoate 0.20 4) 2-Ethylhexanoic acid triglyceride 20.0 5)Magnesium ascorbyl phosphate 2.00 6) Purified water 61.8

(Production Method of Example 40)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and theresulting solution was added with stirring to 6) in which 5) waspreviously dissolved, to obtain the objective milky lotion 25.

Comparative Example 16

Milky Lotion 26 Comparative Example 16 1) γ-Tocopherol 5.00 2)Hydrogenated soybean phospholipid 10.0 3) Methyl parahydroxybenzoate0.20 4) 2-Ethylhexanoic acid triglyceride 20.0 5) Sodium ascorbylphosphate 2.00 6) Purified water 61.8

(Production Method of Comparative Example 16)

Ingredient 1) was uniformly dispersed and dissolved in 2) to 4) and theresulting solution was added with stirring to 6) in which 5) waspreviously dissolved, to obtain the milky lotion 26.

(Results)

Milky lotions 22 to 25 obtained in Examples 37 to 40 gave good feelingon use and exhibited good aging stability. On the other hand, in themilky lotion obtained in Comparative Example 16, phase separation wasobserved after a few days and good aging stability could not beobtained.

Example 41 and Comparative Example 17

Evaluation of Skin Penetrability

(Method)

In each of φ35 mm plastic Petri dishes, 1 ml of a Dulbecco's MEM mediumcontaining 1), 2) or 3) was placed and a nylon mesh and a lens paperwere sequentially laid thereon. On the lens paper, a skin removed fromthe back of a hairless mouse was placed such that the epidermis cameinto contact with the lens paper. At this time, the dermis side wascovered with a parafilm and thereby prevented from drying. 1) Not added2) γ-Tocopherol dimethylglycine ester 0.50 hydrochloride 3) γ-Tocopherolsarcosine ester hydrochloride 0.50

After the passage of 4 hours at 37° C., the skin was washed with aphosphoric acid buffer solution and homogenized. Then, the amount ofγ-tocopherol in the skin was measured. The determination of γ-tocopherolwas performed by high performance liquid chromatography.

The conditions for measurement by high performance liquid chromatographywere as follows.

-   -   Column: Shodex ODSpak F-411    -   Temperature: 40° C.    -   Eluent: methanol/acetonitrile=7/3 (containing 0.02M acetic acid        and 0.02M sodium acetate)    -   Flow rate: 0.7 ml    -   Detection: fluorescent, Ex: 298 nm, Em: 325 nm        (Results)    -   1) lower than detection limit    -   2) 20 nmol/g of skin    -   3) 2.1 nmol/g of skin

The skin treated with γ-tocopherol dimethylglycine ester hydrochlorideor γ-tocopherol sarcosine ester hydrochloride had significant increaseof the γ-tocopherol amount.

Example 42 and Comparative Example 18.

Conversion to γ-Tocopherol in Keratinocyte of Human Epidermis

(Method)

Commercially available keratinocytes of normal human epidermis werecultured in the medium attached. The cells were harvested and spalled byfreeze-thawing method. To this cell spall solution, 1), 2) or 3) wasadded to have a final concentration of 1 mM. The resulting solution waskept at 37° C. for 2 hours and then the amount of γ-tocopherol liberatedin the reaction solution was measured. The determination of γ-tocopherolwas performed by high performance liquid chromatography.

The conditions for measurement by high performance liquid chromatographywere as follows.

-   -   Column: Shodex ODSpak F-411    -   Temperature: 40° C.    -   Eluent: methanol/acetonitrile=7/3 (containing 0.02M acetic acid        and 0.02M sodium acetate)    -   Flow rate: 0.7 ml    -   Detection: fluorescent, Ex: 298 nm, Em: 325 nm

-   1) Not added

-   2) γ-Tocopherol dimethylglycine ester hydrochloride

-   3) γ-Tocopherol sarcosine ester hydrochloride    (Results)    -   1) lower than detection limit    -   2) 28.1 nmol/ml of cell suspension    -   3) 30.3 nmol/ml of cell suspension

The cell spall solution in which γ-tocopherol dimethylglycine esterhydrochloride or γ-tocopherol sarcosine ester hydrochloride was added,had significant increase of the γ-tocopherol amount.

Permeability of Three Dimensional Model of Human Skin Tissue andTocopherol Conversion

40 μL of a 1% solution of the below test substances 1) to 7) dissolvedor dispersed in Dulbecco's PBS (−) were applied onto the tissue surfaceof a three dimensional model of human skin tissue (TESTSKIN™ LSD-d,Toyobo K. K.) and were cultured at 37° C. under 5% CO₂ for 6 hours.After this, the solutions of the test substances were removed byaspiration and sampling was carried out.

The sample model skin was washed with Dulbecco's PBS (−) and the tissuesurfaces onto which the test substances were applied were punched outwith a φ 6 mm punch, and were homogenated in a HEPES buffer solution (pH7.2), and quantitative analysis of the α-tocopherol and γ-tocopherolwere carried out by high speed liquid chromatography. Quantitativeanalysis of the amount of protein in the model skin was carried outaccording to the Lowry method.

-   -   1) α-tocopherol dimethylglycine ester hydrochloride    -   2) α-tocopherol sarcosine ester hydrochloride    -   3) αa-tocopherol glycine ester    -   4) γ-tocopherol dimethylglycine ester hydrochloride    -   5) γ-tocopherol sarcosine ester hydrochloride    -   6) γ-tocopherol glycine ester    -   7) tocopherol acetate

The high speed liquid chromatography measurement conditions were asdescribed below.

-   -   Column: Shodex ODSpak F-411    -   Temperature: 40° C.    -   Eluant: methanol/acetonitrile=7/3 (including 0.02 M acetic acid,        0.02 M sodium acetate)    -   Flow rate: 0.7 ml    -   Detection: fluorescence, Ex 298 mm, Em 325 mm

The amounts of α-tocopherol and γ-tocopherol for the samples processedwith each test substance were as follows.

-   -   1) 2.8 nmol/mg protein (the amount of α-tocopherol)    -   2) 3.9 nmol/mg protein (the amount of α-tocopherol)    -   3) 1.2 nmol/mg protein (the amount of α-tocopherol)    -   4) 4.7 nmol/mg protein (the amount of γ-tocopherol)    -   5) 5.5 nmol/mg protein (the amount of γ-tocopherol)    -   6) 1.5 nmol/mg protein (the amount of γ-tocopherol)    -   7) 1.0 nmol/mg protein (the amount of α-tocopherol)

For the processes carried out using α-tocopherol dimethylglycine esterhydrochloride, α-tocopherol sarcosine ester hydrochloride, γ-tocopheroldimethylglycine ester hydrochloride, and γ-tocopherol sarcosine esterhydrochloride, the level of tocopherol was significantly increased.

INDUSTRIAL APPLICABILITY OF THE INVENTION

The skin preparation for external application of the present inventioncomprising a tocopherol aminoalkylcarboxylate ester having a substituenton the N atom and/or a salt thereof is favored with improved solubilityand emulsifiability of tocopherol and efficient conversion to activetocopherol in skin tissue and therefore, can be applied over a widerange such as skin preparations for external application and cosmeticmaterials.

1. A skin preparation for external application, comprising a tocopherolaminoalkylcarboxylate ester having a substituent on the N atom and/or asalt thereof.
 2. The skin preparation for external application accordingto claim 1, wherein the tocopherol aminoalkylcarboxylate ester is one ormore compound selected from α-tocopherol derivatives, β-tocopherolderivatives, γ-tocopherol derivatives and δ-tocopherol derivatives. 3.The skin preparation for external application according to claim 2,wherein the tocopherol aminoalkylcarboxylate ester is an α-tocopherolaminoalkylcarboxylate ester or a γ-tocopherol aminoalkylcarboxylateester.
 4. The skin preparation for external application according toclaim 1, wherein the tocopherol aminoalkylcarboxylate ester having asubstituent on the N atom comprises a compound represented by formula(I):

(wherein R¹ and R² may be the same or different and each represents alower alkyl group or a hydrogen atom, R³ and R⁴ each represents ahydrogen atom or a methyl group and R represents a branched or linearalkylene group which may have a substituent, provided that R¹ and R² arenot a hydrogen atom at the same time).
 5. The skin preparation forexternal application according to claim 4, wherein the tocopherolaminoalkylcarboxylate ester having a substituent on the N atom comprisesa compound represented by formula (II):

(wherein R¹ and R² may be the same or different and each represents alower alkyl group or a hydrogen tom, R³ and R⁴ each represents ahydrogen atom or a methyl group, and n represents an integer of 1 to 7,provided that R¹ and R² are not a hydrogen atom at the same time). 6.The skin preparation for external application according to claim 4,wherein the aminoalkylcarboxylic acid of the tocopherolaminoalkylcarboxylate ester having a substituent on the N atom is acompound selected from the group consisting of glycine, alanine,β-alanine, valine, leucine, isoleucine, phenylalanine, methionine,cysteine, serine, threonine, tyrosine, thyroxine, histidine, proline,4-hydroxyproline, aspartic acid, glutamic acid and their N-alkylderivatives and N,N-dialkyl derivatives.
 7. The skin preparation forexternal application according to claim 1, wherein theaminoalkylcarboxylic acid of the tocopherol aminoalkylcarboxylate esterhaving a substituent on the N atom has a monoamino group and themonoamino group is a monoalkylamino group.
 8. The skin preparation forexternal application according to claim 1, wherein theaminoalkylcarboxylic acid of the tocopherol aminoalkylcarboxylate esterhaving a substituent on the N atom has a monoamino group and themonoamino group is a dialkylamino group.
 9. The skin preparation forexternal application according to claim 7, wherein the tocopherolaminoalkylcarboxylate ester having a substituent on the N atom is anN,N-dimethylglycine ester of tocopherol.
 10. The skin preparation forexternal application according to claim 8, wherein the tocopherolaminoalkylcarboxylate ester having a substituent on the N atom is atocopherol sarcosine ester.
 11. The skin preparation for externalapplication according to claim 1, wherein the salt is a hydrohalogenicacid salt.
 12. The skin preparation for external application accordingto claim 11, wherein the hydrohalogenic acid is hydrochloric acid. 13.The skin preparation for external application according to any one ofthe claims 1 to 12, wherein the content of the tocopherolaminoalkylcarboxylate ester having a substituent on the N atom and/or asalt thereof is from 0.01 to 10 mass %.
 14. A cosmetic materialcomprising the skin preparation for external application according toclaim 1.